Polymeric microspheres are successfully used for controlled- or sustained-release delivery of some active agents comprising therapeutics such as chemical drugs or therapeutic peptides. This type of dosage forms has also been used in the attempts to achieve controlled- or sustained-release delivery of proteins. The ability of polymeric microspheres to control or retard release rate of the active or therapeutic ingredients loaded wherein offers a great compliance improvement to patients who have to receive frequent injections of medicine for prolonged period or even life time. With controlled- or sustained-release functions, the in vivo concentration of the medicines (drugs or vaccines) may well be maintained within the therapeutic window (a situation of which in vivo level of a drug/medicine is above the minimum effective concentration but below the minimum toxic concentration). The frequency of the hateful injections may therefore be greatly reduced.
Accompany with the benefits above are some drawbacks. A major challenge for preparing protein-loaded microsphere dosage forms is their sterilization process. Microspheres for sustained-release delivery of biologics are normally 10˜100 μm in diameter so that they cannot be sterilized by filtration through a membrane 0.2 μm in pore sizes, a method for sterilizing proteins conventionally. Radiation and heating are out of question too due to the susceptibility of proteins and many other therapeutic agents to such hazardous conditions which result in denaturing and/or degradation of the ingredients. The only feasible method to prepare sterilized microspheres for controlled- or sustained-release delivery of proteins is to prepare this type of dosage forms under an aseptic condition, i.e. to incorporate the whole preparation process in an aseptic environment. Current manufacturing processes produce microspheres of relatively diversified diameters for which pre-lyophilization, sieving and powder-filling become necessary. Sieving and powder-filling are unit operations during which the medical products are exposed to the ambience and difficult to be isolated within an aseptic environment. Moreover, the needs of saving to remove particles of undesired sizes results in reduced yield of manufacture, and powder-filling is difficult to achieve accurate load and requires sophisticated machines. In addition to size dispersion, stirring, a unit operation to prevent microsphere fusion in the present production process, may also result in leaking of the encapsulated. The shear stress generated from stirring may break the newly formed microspheres and expose the encapsulated ingredients to the continuous phase as well as the water-oil (organic phase) interface, a factor known to denature proteins. In addition, under-sized particles are regarded as a source of burst release, and the over-sized microspheres may block the injection needle unless hateful larger needles are selected.
While sustained-release microsphere is the only practical dosage form to date to achieve pro-longed efficacy over two weeks or longer by single injection, this dosage form is used limited drugs due to its production difficulties and other drawbacks. Clearly, a preparation process which enable manufacturer to produce microspheres of uniform and designable particle sizes, and to fill vials with the medicine in a fluid form will be greatly helpful for sterilized manufacturing.